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Nathan Alexander Lambert-Cheatham, Sheik Pran Babu Sardar Pasha, Bomina Park, Sangil Kwon, Sydney Waller, Bit Lee, Seung-Yong Seo, Timothy William Corson; A novel ferrochelatase inhibitor decreases murine laser-induced choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3978.
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© ARVO (1962-2015); The Authors (2016-present)
New treatments are needed to address cases of neovascular age related macular degeneration (nAMD) refractive to standard therapy. The enzyme ferrochelatase (FECH) is a new potential target for the treatment of choroidal neovascularization (CNV) in conditions such as nAMD. We tested the novel FECH inhibitor, SH-17023, on CNV lesion size in a murine laser-induced choroidal neovascularization (L-CNV) model to determine the potential efficacy of the compound.
Adult C57BL/6J mice (7-8 week old, female) were used for the experiment. The Micron IV green argon laser was used to burn 4 Bruch’s membrane holes in each mouse retina to induce CNV generation. Immediately following laser treatment, all mice received 0.5 µL intravitreal injections of either low dose SH-17023 (50 µM), higher dose SH-17023 (100 µM), or vehicle (0.5% DMSO in PBS). At 7 and 14 days post-treatment, the lesions were imaged using optical coherence tomography (OCT) and fundus photography. On day 14 mice also received fluorescein angiography to assess vascular leakage from CNV lesions. Following imaging on day 14, the mice were sacrificed and their eyes were enucleated. Choroidal flat mounts from the mouse eyes were stained for agglutinin and isolectin GS-IB4 and imaged by confocal microscopy. ImageJ was used to quantify lesion volume in both OCT and confocal images. ANOVA with Dunnett’s post hoc test was used for statistical analysis of lesion volume.
Confocal images of choroids stained with GS-IB4 and agglutinin revealed a significant decrease in CNV lesion volume for both low dose and higher dose SH-17023 compared to vehicle (P<0.0001). Similarly, OCT images revealed a significant decrease in lesion size for higher dose SH-17023 compared to vehicle (P=0.0084), with a trend towards significance for low dose SH-17023 (P=0.0539). Fluorescein angiograms revealed leakage from all CNV lesions. There was no obvious toxicity from the compound seen on fundus and OCT imaging.
OCT and confocal microscopy showed that SH-17023 is capable of reducing CNV lesion size after a single intravitreal injection in a murine L-CNV model. Further analysis of SH-17023 in pharmacokinetic studies, toxicology studies, and other models of CNV will be valuable in determining the compound’s clinical potential for nAMD therapy.
This is a 2020 ARVO Annual Meeting abstract.
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